P-Slide P-Slide 1 Neuropharmacology of Neuropharmacology of Antiepileptic Drugs Antiepileptic Drugs American Epilepsy Society
Dec 23, 2015
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Neuropharmacology of Neuropharmacology of Antiepileptic DrugsAntiepileptic Drugs
American Epilepsy Society
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DefinitionsDefinitions
Seizure: the clinical manifestation of an abnormal synchronization and excessive excitation of a population of cortical neurons
Epilepsy: a tendency toward recurrent seizures unprovoked by acute systemic or neurologic insults
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Antiepileptic DrugAntiepileptic Drug
A drug which decreases the frequency and/or severity of seizures in people with epilepsy
Treats the symptom of seizures, not the underlying epileptic condition
Goal—maximize quality of life by minimizing seizures and adverse drug effects
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History of Antiepileptic History of Antiepileptic Drug Therapy in the U.S.Drug Therapy in the U.S.
1857 - Bromides
1912 - Phenobarbital
1937 - Phenytoin
1954 - Primidone
1960 - Ethosuximide
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History of Antiepileptic History of Antiepileptic Drug Therapy in the U.S.Drug Therapy in the U.S.
1974 - Carbamazepine
1975 - Clonazepam
1978 - Valproate
1993 - Felbamate, Gabapentin
1995 - Lamotrigine
1997 - Topiramate, Tiagabine
1999 - Levetiracetam
2000 - Oxcarbazepine, Zonisamide
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Antiepileptic Drug TherapyAntiepileptic Drug TherapyStructures of Commonly Used AEDsStructures of Commonly Used AEDs
Chemical formulas of commonly used old and new antiepileptic drugs
Adapted from Rogawski and Porter, 1993, and Engel, 1989
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Antiepileptic Drug TherapyAntiepileptic Drug TherapyStructures of Commonly Used AEDsStructures of Commonly Used AEDs
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Antiepileptic Drug TherapyAntiepileptic Drug TherapyStructures of Commonly Used AEDsStructures of Commonly Used AEDs
LevetiracetamLevetiracetam
OxcarbazepineOxcarbazepine
ZonisamideZonisamide
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Antiepileptic Drug TherapyAntiepileptic Drug TherapyStructures of Commonly Used AEDsStructures of Commonly Used AEDs
Pregabalin
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Cellular Mechanisms of Cellular Mechanisms of Seizure GenerationSeizure Generation
Excitation (too much)
• Ionic-inward Na+, Ca++ currents
• Neurotransmitter: glutamate, aspartate
Inhibition (too little)
• Ionic-inward CI-, outward K+ currents
• Neurotransmitter: GABA
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AEDs: Molecular and AEDs: Molecular and Cellular MechanismsCellular Mechanisms
Phenytoin, Carbamazepine• Block voltage-dependent sodium channels at high firing
frequencies
Barbiturates• Prolong GABA-mediated chloride channel openings
• Some blockade of voltage-dependent sodium channels
Benzodiazepines• Increase frequency of GABA-mediated chloride channel
openings
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AEDs: Molecular and AEDs: Molecular and Cellular MechanismsCellular Mechanisms
Felbamate • May block voltage-dependent sodium channels at high
firing frequencies• May modulate NMDA receptor via strychnine-insensitive
glycine receptor
Gabapentin• Increases neuronal GABA concentration• Enhances GABA mediated inhibition
Lamotrigine• Blocks voltage-dependent sodium channels at high firing
frequencies• May interfere with pathologic glutamate release
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AEDs: Molecular and AEDs: Molecular and Cellular MechanismsCellular Mechanisms
Ethosuximide• Blocks low threshold, “transient” (T-type) calcium channels
in thalamic neurons
Valproate• May enhance GABA transmission in specific circuits
• Blocks voltage-dependent sodium channels
Vigabatrin• Irreversibly inhibits GABA-transaminase
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AEDs: Molecular and AEDs: Molecular and Cellular MechanismsCellular Mechanisms
Topiramate• Blocks voltage-dependent sodium channels at high firing
frequencies
• Increases frequency at which GABA opens Cl- channels (different site than benzodiazepines)
• Antagonizes glutamate action at AMPA/kainate receptor subtype
• Inhibition of carbonic anydrase
Tiagabine• Interferes with GABA re-uptake
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AEDs: Molecular and AEDs: Molecular and Cellular MechanismsCellular Mechanisms
Levetiracetam• Binding of reversible saturable specific binding site
• Reduces high-voltsge- activated Ca2+ currents
• Reverses inhibition of GABA and glycine gated currents induced by negative allosteric modulators
Oxcarbazepine• Blocks voltage-dependent sodium channels at high firing frequencies
• Exerts effect on K+ channels
Zonisamide• Blocks voltage-dependent sodium channels and
T-type calcium channels
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AEDs: Molecular and AEDs: Molecular and Cellular MechanismsCellular Mechanisms
Pregabalin• Increases neuronal GABA
• Increase in glutamic acid decarboxylase
• Decrease in neuronal calcium currents by binding of alpha 2 delta subunit of the voltage gated calcium channel
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The GABA SystemThe GABA System
The GABA system and its associated chloride channel
From Engel, 1989
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Pharmacokinetic PrinciplesPharmacokinetic Principles
Absorption: entry of drug into the blood
• Essentially complete for all AEDs (except gabapentin)
• Timing varies widely by drug, formulation,patient characteristics
• Generally slowed by food in stomach (CBZ may be exception)
• Usually takes several hours (importance for interpreting blood levels)
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The Cytochrome P-450 The Cytochrome P-450 Enzyme SystemEnzyme System
Inducers Inhibitors
phenobarbital erythromycin
primidone nifedipine/verapamil
phenytoin trimethoprim/sulfa
carbamazepine propoxyphene
tobacco/cigarettes cimetidine
valproate
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The Cytochrome P-450 The Cytochrome P-450 Enzyme SystemEnzyme System
Substrates (metabolism enhanced by inducers):
steroid hormones
theophylline
tricyclic antidepressants
vitamins
warfarin
(many more)
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The Cytochrome P-450 The Cytochrome P-450 Isozyme SystemIsozyme System
The enzymes most involved with drug metabolism
Nomenclature based upon homology of amino acid sequences
Enzymes have broad substrate specificity, and individual drugs may be substrates for several enzymes
The principle enzymes involved with AED metabolism include CYP2C9, CYP2C19, CYP3A4
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Drug Metabolizing Enzymes: Drug Metabolizing Enzymes: UDP- Glucuronyltransferase (UGT)UDP- Glucuronyltransferase (UGT)
Important pathway for drug metabolism/inactivation
Currently less well described than CYP
Several isozymes that are involved in AED metabolism include: UGT1A9 (VPA), UGT2B7 (VPA, lorazepam), UGT1A4 (LTG)
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Drug Metabolizing Drug Metabolizing Isozymes and AEDsIsozymes and AEDs
AED CYP3A4 CYP2C9 CYP2C19 UGT
CBZ +
PHT + +
VPA + +
PB +
ZNS +
TGB +
AEDs that do not appear to be either inducers or inhibitors of the CYP AEDs that do not appear to be either inducers or inhibitors of the CYP system include: gabapentin, lamotrigine, tiagabine, levetiracetam, system include: gabapentin, lamotrigine, tiagabine, levetiracetam, zonisamide.zonisamide.
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Enzyme Inducers/Inhibitors: Enzyme Inducers/Inhibitors: General ConsiderationsGeneral Considerations
Inducers: Increase clearance and decrease steady-state concentrations of other substrates
Inhibitors: Decrease clearance and increase steady-state concentrations of other substrates
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Pharmacokinetic PrinciplesPharmacokinetic Principles
Elimination: removal of active drug from the blood by metabolism and excretion• Metabolism/biotransformation — generally hepatic; usually
rate-limiting step
• Excretion — mostly renal
• Active and inactive metabolites
• Changes in metabolism over time (auto-induction with carbamazepine) or with polytherapy (enzyme induction or inhibition)
• Differences in metabolism by age, systemic disease
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AED Inducers: General AED Inducers: General ConsiderationsConsiderations
Results from synthesis of new enzyme
Tends to be slower in onset/offset than inhibition interactions
Broad Spectrum Inducers:
Carbamazepine
Phenytoin
Phenobarbital/primidone
Selective CYP3A Inducers:
Felbamate, Topiramate, Oxcarbazepine
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InhibitionInhibition
Competition at specific hepatic enzyme site
Onset typically rapid and concentration (inhibitor) dependent
Possible to predict potential interactions by knowledge of specific hepatic enzymes and major pathways of AED metabolism
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AED InhibitorsAED Inhibitors
Valproate UDP glucuronosyltransferase (UGT)
plasma concentrations of Lamotrigine, Lorazepam CYP2C19
plasma concentrations of Phenytoin, Phenobarbital
Topiramate & Oxcarbazepine CYP2C19
plasma concentrations of Phenytoin
Felbamate CYP2C19
plasma concentrations of Phenytoin, Phenobarbital
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Hepatic Drug Metabolizing Hepatic Drug Metabolizing Enzymes and Specific AED Enzymes and Specific AED InteractionsInteractions
Phenytoin CYP2C9 CYP2C19
Inhibitors: valproate, ticlopidine, fluoxetine, topiramate, fluconazole
Carbamazepine CYP3A4 CYP2C8 CYP1A2
Inhibitors: ketoconazole, fluconazole, erythromycin, diltiazem
Lamotrigine UGT 1A4
Inhibitor: valproate
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Isozyme Specific Drug Isozyme Specific Drug InteractionsInteractionsCategory CYP3A4 CYP2C9 CYP2C19 UGT
Inhibitor ErythromycinClarithromycinDiltiazemFluconazoleItraconazoleKetoconazoleCimetidinepropoxypheneGrapefruitjuice
VPAFluconazolemetronidazoleSertralineParoxetineTrimethoprim/sulfa
TiclopidineFelbamateOXC/MHDOmeprazole
VPA
Inducer CBZPHTPBfelbamateRifampinTPMOXC/MHD
CBZPHTPBRifampin
CBZPHTPBrifampin
CBZPHTPBOXC/MHDLTG (?)
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Therapeutic IndexTherapeutic Index
T.I. = ED 5O% /TD 50%
“Therapeutic range” of AED serum concentrations
• Limited data
• Broad generalization
• Individual differences
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AED Serum ConcentrationsAED Serum Concentrations
In general, AED serum concentrations can be used as a guide for evaluating the efficacy of medication therapy for epilepsy.
Serum concentrations are useful when optimizing AED therapy, assessing compliance, or teasing out drug-drug interactions.
They should be used to monitor pharmacodynamic and pharmacokinetic interactions.
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AED Serum ConcentrationsAED Serum Concentrations
Serum concentrations are also useful when documenting positive or negative outcomes associated with AED therapy.
Most often individual patients define their own “ therapeutic range” for AEDs.
For the new AEDs there is no clearly defined “therapeutic range”.
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Potential Target Range of AED Potential Target Range of AED Serum ConcentrationsSerum Concentrations
AED Serum Concentration
(mg/l)
Carbamazepine 4-12
Ethosuximide 40-100
Phenobarbital 10-40
Phenytoin 10-20
Valproic acid 50-100
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Potential Target Range of AED Potential Target Range of AED Serum ConcentrationsSerum Concentrations
AED Serum Concentration
(mg/l)
Gabapentin 6-21
Lamotrigine 5-18
Levetiracetam 10-40
Oxcarbazepine 12-24 (MHD)
Pregabalin ??
Tiagabine ?
Topiramate 4.0-25
Zonisamide 7-40
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AEDs and Drug InteractionsAEDs and Drug Interactions
Although many AEDs can cause pharmacokinetic interactions, several agents appear to be less problematic.
AEDs that do not appear to be either inducers or inhibitors of the CYP system include:
GabapentinLamotriginePregabalinTiagabineLevetiracetamZonisamide
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Pharmacodynamic InteractionsPharmacodynamic Interactions
Wanted and unwanted effects on target organ
• Efficacy — seizure control
• Toxicity — adverse effects (dizziness, ataxia, nausea, etc.)
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Pharmacokinetic Interactions: Pharmacokinetic Interactions: Possible Clinical ScenariosPossible Clinical Scenarios
Be aware that drug interactions may
occur when:
Addition of a new medication when inducer/inhibitor is present
Addition of inducer/inhibitor to existing medication regimen
Removal of an inducer/inhibitor from chronic medication regimen
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Pharmacokinetic Factors Pharmacokinetic Factors in the Elderlyin the Elderly
Absorption — little change
Distribution
• decrease in lean body mass important for highly lipid-soluble drugs
• fall in albumin leading to higher free fraction
Metabolism — decreased hepatic enzyme content and blood flow
Excretion — decreased renal clearance
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Pharmacokinetic Factors Pharmacokinetic Factors in Pediatricsin Pediatrics
Neonate—often lower per kg doses
• Low protein binding
• Low metabolic rate
Children—higher, more frequent doses
• Faster metabolism
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Pharmacokinetics in PregnancyPharmacokinetics in Pregnancy
Increased volume of distribution
Lower serum albumin
Faster metabolism
Higher dose, but probably less than predicted by total level (measure free level)
Consider more frequent dosing
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Adverse EffectsAdverse Effects
Acute dose-related—reversible
Idiosyncratic—• uncommon rare
• potentially serious or life threatening
Chronic—reversibility and seriousness vary
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Acute, Dose-Related Adverse Acute, Dose-Related Adverse Effects of AEDsEffects of AEDs
Neurologic/Psychiatric – most common Sedation, fatigue
Unsteadiness, uncoordination, dizziness
Tremor
Paresthesia
Diplopia, blurred vision
Mental/motor slowing or impairment
Mood or behavioral changes
Changes in libido or sexual function
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Acute, Dose-Related Adverse Acute, Dose-Related Adverse Effects of AEDs (cont.)Effects of AEDs (cont.)
Gastrointestinal (nausea, heartburn)
Mild to moderate laboratory changes Hyponatremia (may be asymptomatic)
Increases in ALT or AST
Leukopenia
Thrombocytopenia
Weight gain/appetite changes
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Idiosyncratic Adverse Idiosyncratic Adverse Effects of AEDsEffects of AEDs
Rash, Exfoliation
Signs of potential Stevens-Johnson syndrome Hepatic Damage
Early symptoms: abdominal pain, vomiting, jaundice
Laboratory monitoring probably not helpful in early
detection
Patient education
Fever and mucus membrane involvement
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Idiosyncratic Adverse Idiosyncratic Adverse Effects of AEDs Effects of AEDs
Hematologic Damage
(marrow aplasia, agranulocytosis) Early symptoms: abnormal bleeding, acute onset of fever,
symptoms of anemia
Laboratory monitoring probably not helpful in early
detection
Patient education
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Long-Term Adverse Long-Term Adverse Effects of AEDsEffects of AEDs
Neurologic: Neuropathy
Cerebellar syndrome
Endocrine/Metabolic Effects Vitamin D – Osteomalacia, osteoporosis Folate – Anemia, teratogenesis Altered connective tissue metabolism or growth
Facial coarsening Hirsutism Gingival hyperplasia
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Pharmacology ResidentPharmacology ResidentCase StudiesCase Studies
American Epilepsy Society
Medical Education Program
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Pharmacology ResidentPharmacology ResidentCase StudiesCase Studies
Tommy is a 4 year old child with a history of intractable seizures and developmental delay since birth.
He has been tried on several anticonvulsant regimens (i.e., carbamazepine, valproic acid, ethosuximide, phenytoin, and phenobarbital) without significant benefit.
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Case #1 – Pediatric Con’tCase #1 – Pediatric Con’t
Tommy’s seizures are characterized as tonic seizures and atypical absence seizures and has been diagnosed with a type of childhood epilepsy known as Lennox-Gastaut Syndrome.
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Case #1 – Pediatric Con’tCase #1 – Pediatric Con’t
1. Briefly describe what characteristics are associated with Lennox-Gastaut Syndrome.
2. What anticonvulsants are currently FDA approved for Lennox-Gastaut Syndrome?
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Case #1 – Pediatric Con’tCase #1 – Pediatric Con’t
3. Tommy is currently being treated with ethosuximide 250 mg BID and valproic acid 250 mg BID. The neurologist wants to add another anticonvulsant onto Tommy’s current regimen and asks you for your recommendations. (Hint: Evaluate current anticonvulsants based on positive clinical benefit in combination therapy and adverse effect profile.)